Prostate Cancer
Prostate cancer is the most common cancer in males over sixty in developed countries. Current estimates of new prostate cancer cases in North America are about 300,000 per year, of which approximately 40,000 will succumb to the disease. The etiology of prostate cancer is still not well understood but progression of benign hyperplasia to overt cancer requires co-ordinate changes in cell cycle and apoptosis and deregulation of negative growth regulating factors. Primary prostate cancer is curable by radical prostatectomy but the metastatic disease is refractory to most common forms of therapy.
Most deaths from prostate cancer, however, are due to metastatic disease that, in general, does not respond with good curative rates, to chemotherapy or radiation. Hormonal depletion either by physical or chemical castration by the use of gonadotrophin releasing hormone analogues, exogenous estrogens, antiandrogens, progestational agents or adrenal enzyme synthesis inhibitors such as ketoconazole and aminoglutethimide has been for long the major mode of treatment for prostate cancer. Since several different organs such as the hypothalamus, pituitary, adrenal gland, testes and the prostate are involved in modulating the biochemical effects of androgens, removal of the testis removes only 40% of the total secretory hormone and as such chemical anti-hormone therapy is the preferred mode of treatment. The major drawback, apart from the toxicity side effects, is the generation of highly aggressive hormone independent cells that are refractory to anti-hormone therapy. Treatment modalities that can target both hormone sensitive as well as hormone insensitive cells are likely to have greater success and is one of the major challenges in the therapy of prostate cancer.
Other classes of anti-prostate cancer drugs are currently in use (reviewed in Osterlink et al., in Cancer: Principles and Practice of Oncology, DeVita, V. T., Hellman, S., Rosenberg, S. A., Lippincott-Raven, 1997, pp. 1322-1375). Some examples include growth factor inhibitors such as suramin or estramustine that affects microtubule assembly and affects nuclear matrix, a key determinant of chromatin structure and nuclear shape. Reports on the efficacy of suramin, a compound that affects binding of growth factor with its receptor and adrenal steroidogenesis is mixed and the major drawback in its use either singly or in combination with hydrocortisone seems to exhibit toxicities ranging from myelopathy, vortex keratopathy and coagulopathy. Vinca alkaloids that also target the microtubule assembly, vinblastine and navelbine, have shown modest activities whereas cytoskeletal disrupting agents etoposide and paciltaxel that do not show much activity as single agents but have been to shown to synergize with estramustine. Other combination therapies currently being evaluated include cyclophosphamide plus GM-CSF and ketoconazole plus doxorubicin.
Therapeutic attempts have also been made with mitoxantrone. Mitoxantrone has modest activity alone in patients with advanced prostate cancer but can provide significant palliation when combined with prednisone with respect to pain relief and quality of life end point (Wiseman, 1997, Drugs Aging 10:473-485 and Smith, 2000, J. Urol. 163:248). Mitoxantrone and prednisone are the only FDA approved treatment combinations approved for hormone refractory prostate cancer. Myelosuppression and neutropenia are the major toxicities that are developed.
Other approaches currently under investigation include immunological approaches using prostate specific antigen (PSA) and cytokines such as IL-2, IL-6, IL-7, GM-CSF and TNF and the use of angiogenesis inhibitors. The neovasculature in endothelial cells is a therapeutic target for an antiangiogenic agent.
Acridines
A number of derivatives of acridine have been studied for antitumor activity. Earlier work showed that 1-nitro-9-alkylaminoalkylaminoacridines had good antitumor activity (see, for example, U.S. Pat. No. 4,139,531, Gniazdowsk et al., 1995, Gen. Pharmacol. 26:473, Ledochowski, 1976, Mat. Med. Pol. 8:237, Mazerska et al., 1984, Eur. J. Med. Chem. 19:199, Pawlak et al., 1984, Cancer Res. 44:4829, EP 38572).
Compositions of acridines and other antitumor agents have been formulated. For example, U.S. Pat. No. 5,891,864 discloses anti-cancer compositions comprising acridine derivatives and a guanosine compound. Compounds specifically disclosed include acriflavine neutral, acriflavine, acridine orange, acridine yellow G, diacridine, aniline mustard, guanosine, guanosine hydrate and isoguanosine. It is stated that acridine compounds alone have a small anti-cancer effect and guanosine compounds have none, so the guanosine compounds boost the anti-cancer effect of the acridine derivatives. It is noted that these compositions may be used to treat lung cancer, hepatoma, leukemia, solid tumor and epithelial tissue carcinomas. It is also mentioned that the compositions may also comprise an enhanced anti-tumor effective amount of an immunomodulator, anti-tumor agent or pharmaceutically acceptable carrier.
U.S. Pat. No. 5,759,514 discloses a conjugate for tumor therapy comprising a tumor cell-targeting protein or polypeptide and a radiolabeled nucleic acid-targeting small molecule. This conjugate may bind to the surface of the tumor cell and is subsequently endocytosed. The conjugate once endocytosed, may be lytically decomposed to the radiolabeled small molecule. This radiolabeled small molecule may enter the nucleus of the tumor cell. The small molecule may bind to the tumor cell nucleic acid and the radiolabel may decompose the tumor cell nuclei. The tumor cell targeting protein or polypeptide includes an antibody or fragment thereof, polypeptide hormone or growth factor. The small molecule may be a fluorescein, an acridine such as 3-acetamido-5-iodo-6-aminoacridine or nitracrine, a diacridine, ethidium bromide derivatives, phenanthridines, anthracyclines, and quinazoline derivatives. The radiolabel is an Auger electron-emitting radioisotope such as 125I, 32P, 188Rh, 131I, 77Br, 225At, and 213Bi. These conjugates are tested in carcinoma cells.
U.S. Pat. No. 5,696,131 discloses the use of acridine carboxamides in combination with other cytotoxic drugs for treating leukemia, melanoma, testicular, brain, ovarian, lung, advanced colon and breast cancer. Additionally, it is disclosed that acridine carboxamides may be used in combination with another cytotoxic drug, such as a DNA reactive reagent (e.g., cisplatin, cyclophosphamide, bleomycin and carboplatin), a DNA synthesis inhibitor (5-fluorouracil, 5-fluorodeoxyuridine and methotrexate) or an agent which disrupts the mitotic apparatus (taxol and vinca alkaloids) to circumvent multidrug resistance. Furthermore, it is proposed that these compounds may be used with a “rescue” treatment with a second drug that by itself is not an active agent but displaces the acridine carboxamide from the DNA.
U.S. Pat. No. 5,604,237 discloses acridine analogs with nitro at the 1-position, a ketone at the 9-position and optionally methoxy at the 7-position. Furthermore, the patent discloses compositions comprising these compounds to improve or increase the efficacy of an antitumor drug such as Vinca alkaloids, anthracyclines, taxol and derivatives thereof, podophyllotoxins, mitoxantrone, actinomycin, colchicine, gramicidin D, amsacrine, increase or restore sensitivity of a tumor to an antitumor drug or reverse or reduce resistance of a tumor to an antitumor drug. No synergism is disclosed.
U.S. Pat. No. 4,603,125 describes antitumor acridine analogs and pharmaceutical compositions containing these analogs. isotonic and absorption delaying agents and the like”.
U.S. Pat. No. 3,694,447 discloses complexes of phosphanilic acid and aminoacridines. These complexes may be used as antibacterial and antifungal agents. The aminoacridine may also have a nitro group on the acridine ring.
Ceci et al., 1996, Inorg. Chem. 35:876 describes results of coordination studies of 1-nitro-9-[2-(dialkylamino)ethylamino]acridines with platinum. This compound appears to be very reactive toward platinum. This is due to the severe steric interactions between the 1-nitro and the 9-alkylamino groups in the peri positions of the acridine ring system.
Gniazdowski et al., 1982, Cancer Letters 15:73 shows that five substituted 1-nitro-9-aminoacridine derivatives show an irreversible thiol-dependent inhibitory effect on RNA synthesis in an in vitro system. In the absence of sulhydryl compounds no inhibitory effect is observed.
Szumiel et al., 1980, Neoplasma 6:697 describes the results of combined treatment with X-rays and nitracrine in murine lymphoma cells. It appears that this combined treatment gave additive effects.